Interictal spikes on the EEG are strongly correlated with a propensity for seizures, but we don't understand why. In this application, we will test the hypothesis that interictal spikes occur as a consequence of monophasic spread of excitation through the epileptic network, while seizures are initiated when excitation spreads via unique, circular paths of excitation. These circular paths engender repeated, reentrant activation of the neural network. To use a cardiac analogy, reentrant activation of the epileptic network arises instead of a spike in the same manner that reentrant cardiac tachyarrhythmias arise instead of a QRS complex. This hypothesis has three testable components 1) there are multiple paths by which excitation may spread from a stochastic site of spike onset to the rest of the epileptic network. 2) Which path is followed depends on interactions between the onset site and changes in network circuitry induced by dysgenesis, injury, and transient local refractoriness 3) Some of these excitation pathways are closed loops, engendering re-entrant waves of excitation that underlie the local rhythmic activity recorded at the start of focal-onset seizures. We will test these hypotheses using in vivo and in vitro electrical and optical recordings of the spread of excitation in neural networks, as well as computer modeling. This project will provide insights into several pressing problems. First, we will better understand how focal seizures start, which may improve our ability to detect and abort them. Second, we may solve the puzzle of the relationship between spikes and seizures. Third, we will be able to study the effect of anticonvulsants on reentrant activity, which may represent the earliest phase of a seizure;this would comprise a new and potentially more informative screen for drug efficacy. Fourth, in analogy to management of cardiac arrhythmias, this research provides the foundation for abortive stimulation or very focal ablation of the specific neural pathways that initiate seizures, making possible less invasive treatment of drug-resistant epilepsy. PUBLIC HEALTH RELEVANCE: One of the most disabling aspects of epilepsy is the unpredictable nature of seizures. This research will help us understand how epileptic seizures start, so that we will be able to predict and abort them. We will also understand how seizures are related to the activity observed on EEGs obtained between seizures. We predict that seizures start by activation of very specific neuronal pathways that can be ablated by surgery;such surgery should be as minimally invasive as the treatment of cardiac arrhythmias by cardiac catheterization. This would enable treatment of seizures arising in areas of the brain subserving language, movement and vision.